The present invention relates to fluorous triphase and other multiphase systems and, especially, to fluorous triphase and other multiphase systems for effecting reactions and/or separations.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
In fluorous biphasic reaction methods, an organic substrate dissolved in an organic solvent and a fluorous catalyst (or precatalyst) dissolved in a fluorous solvent are contacted with any other needed reagents or reactants to form an organic product. Separation of the organic and fluorous liquid phases provides the product from the organic phase and the catalyst from the fluorous phase. See, for example, Horvath, I. T.; Rxc3xa1bai, J. Science, 266, 72 (1994); Horvath, I. T., Acc. Chem. Res., 31, 641 (1998); and U.S. Pat. No. 5,463,082.
Since fluorous biphasic reactions were introduced to organic synthesis by Horvxc3xa1th and Rxc3xa1bai, much attention has been paid to the strategic new option of fluorous techniques for conducting organic reactions and for separating reaction mixtures. A review of fluorous techniques is provided in Curran, D. P., Angew. Chem. Int. Ed. Engl., 37, 1175 (1998). In general, fluorous techniques in organic synthesis can be classified into three categories: (1) fluorous biphasic reactions as described above; (2) fluorous liquid-organic liquid separation; and (3) organic liquid-fluorous solid separation.
Although the usefulness of fluorous techniques has been extended substantially in recent years, it remains very desirable to develop improved fluorous reaction and separation methods and apparatuses.
In one aspect, the present invention provides method of reacting a first compound to produce a second compound including the steps of: contacting a first non-fluorous phase including the first compound with a first fluorous phase at a first phase interface, the first compound distributing between the first fluorous phase and the first non-fluorous phase; contacting the first fluorous phase with a second non-fluorous phase at a second phase interface; and including at least a third compound in the second non-fluorous phase that reacts with the first compound to produce the second compound, the second compound having a distribution coefficient less than the first compound (and preferably distributing preferentially in the second non-fluorous phase). This method can, for example be used to separate the second compound from unreacted first compound wherein, for example, the first compound is of a fluorous nature and distributes more readily into (or transports, diffuses or migrates more quickly through) the fluorous phase than does the second compound. In general, the fluorous phase serves as a barrier to prevent the two non-fluorous phases from mixing, but molecules that can transport, diffuse or migrate through the fluorous phase can pass from one side to the other. As used herein, the term xe2x80x9ctransportxe2x80x9d includes unaided movement, migration or diffusion of a chemical substance or diffusion or migration assisted by a reagent.
The fluorous liquid phase(s) of the present invention can, for example, include any number of fluorous liquids as known in the art, including fluorous solvents. As used herein, the term xe2x80x9cfluorous liquidxe2x80x9d refers generally to a liquid and/or a liquid mixture that is rich in carbon-fluorine bonds. As used herein, the term xe2x80x9cfluorous solventxe2x80x9d refers generally to a solvent and/or a solvent mixture that is rich in carbon-fluorine bonds. Fluorous solvents include fluorocarbons (for example, perfluorohexane and perfluoroheptane), fluorohydrocarbons, fluorinated ethers (for example, perfluorobutyltetrahydrofuran) and fluorinated amines (for example, perfluorotriethyl amine), among others. In general, fluorous liquids and solvents have Hildebrand solubility parameters less than about 14 MPa1/2. Many fluorous liquids and solvents are commercially available, and a partial list of commercially available and otherwise known fluorous liquids and solvents is contained in Barthel-Rosa, L. P.; Gladysz, J. A. xe2x80x9cChemistry in fluorous media: a user""s guide to practical considerations in the application of fluorous catalysts and reagentsxe2x80x9d Coord. Chem. Rev., 192, 587-605 (1999).
As used herein, the term xe2x80x9cliquidxe2x80x9d refers generally to phases that take the shape of their container without necessarily filling it (J. N. Murrell and E. A. Boucher, xe2x80x9cProperties of Liquids and Solutionsxe2x80x9d Wiley, N.Y., 1982, pp1-3). Non-viscous liquids fill a container quickly, while liquid phases with a high viscosity may take a perceptible time to fill a container. Examples of high-viscosity fluorous liquids include, for example, oligomeric mixtures such as the Krytox series available from DuPont.
The term xe2x80x9cliquidxe2x80x9d also includes supported liquids wherein, for example, the liquid is included in the pore space of a macro-porous or micro-porous support (for example, a liquid membrane). The term xe2x80x9cliquidxe2x80x9d further includes gel phases, which are formed, for example, by adding a gelling agent to a liquid phase, and plasticized liquid phases. The term liquid also includes solutions of nominally pure liquids and other chemical species dissolved in or suspended in them. For example, such dissolved species can be other liquids, solids that form a pseudophase (for example, perfluoroalkane sulfonate of perfluoroalkane carboxylate surfactants which may form reverse micelles or other pseudophases), transport agents or carriers (for example, metal chelators, metal complexes, organic molecular receptors or nanoparticles).
Non-fluorous phases of the present invention can generally be any non-fluorous liquid or solvent as known in the art. As used herein, the terms xe2x80x9cnon-fluorous liquidxe2x80x9d and xe2x80x9cnon-fluorous solventxe2x80x9d refers generally to organic and aqueous liquids and solvents, respectively, and/or to mixtures thereof. Preferred non-fluorous liquids have a Hildebrand solubility parameter greater than about 17 MPa1/2, and more preferred non-fluorous liquids have a Hildebrand parameter greater than about 18 MPa1/2. Water and other aqueous liquid mixtures are suitable non-fluorous liquids for use in the present invention, as are many organic liquids including, but not limited to, acetonitrile, ethyl acetate, ethanol, methanol, tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide, toluene and benzene. Non-traditional organic liquids such as ionic liquids can also be used.
In the methods of the present invention, the fluorous mutliphasic system preferably does not become substantially homogeneous at any point in the process. In this regard, the fluorous and non-fluorous phases preferably remain substantially immiscible during the course of the process. However, some mixing or miscibility at the phase boundary (interface) between the fluorous and non-fluorous phases is allowable and may even be helpful to promote the contact of the fluorous and non-fluorous phases and thereby facilitate exchange of certain components between the respective phases. In addition, the non-fluorous phase may distribute into the fluorous phase altering its composition during a reaction, separation or reaction/separation procedure. Likewise, the fluorous phase may distribute into the non-fluorous phase, altering its composition. The conditions for miscibility or immiscibility of many fluorous and non-fluorous liquids and liquid mixtures are well known, and unknown pairings can often be predicted by differences in Hildebrand solubility parameters or can be readily determined experimentally.
In one embodiment, the first non-fluorous phase includes at least one compound other than the first compound. The other compound has a distribution coefficient less than the first compound and preferably distributes preferentially into the first non-fluorous phase. In this embodiment, the other compound(s) can be thought of as impurities. The higher distribution coefficient of the first compound (for example, as a result of increased or greater fluorous nature of the first compound) as compared to the other compound(s) results in a separation of the first compound from such xe2x80x9cimpuritiesxe2x80x9d before and/or during the reaction step without a separate separation step/apparatus.
Preferably, the first compound has a distribution coefficient between approximately 0.01 and approximately 10 (as determined between the first fluorous phase and the first non-fluorous phase). More preferably, the first compound has a distribution coefficient between approximately 0.1 and approximately 5.0. Most preferably, the first compound has a distribution coefficient between approximately 0.5 and approximately 2.0.
As used herein, the distribution coefficient (KD) is defined generally as the total concentration of a substance (for example, a molecule, molecular fragment, compound, ion, or complex) in the fluorous phase divided by the total concentration of the substance in the non-fluorous phase, at equilibrium. An experimental measurement of the concentration of a substance at equilibrium with two immiscible liquid phases yields the distribution coefficient, as shown by the experiments in Examples 1 and 2 of the Experimental Examples set forth below. If that substance does not participate in chemical or physical equilibria other than partitioning, the distribution coefficient is the same as the partition coefficient. The partition coefficient reflects the relative tendency of the substance to dissolve in each of the two immiscible phases at equilibrium. If that substance enters into other chemical or physical equilibria, for example protonation/deprotonation, metal binding/chelation, association with a receptor, micellization, etc., then the distribution coefficient represents the net effect of all of the equilibria; namely the partitioning equilibria and all other chemical and physical equilibria in which the substance takes part. In cases where an equilibrium is not reached, for example, as a result of an ongoing chemical reaction that continually displaces the equilibrium, the measurement of a distribution coefficient may not be practical, and experiments to measure the relative concentrations of a substance instead provide an operational non-equilibrium distribution ratio.
In general, a substance that distributes preferentially into the fluorous phase has a distribution coefficient greater than 1 (and often much greater than 1), and a substance that distributes preferentially into a non-fluorous phase (for example, an organic phase) has a distribution coefficient less than 1 (and often much less than 1).
To effect separation, the distribution coefficient(s) of one or more compounds other than the first compound (as measured between the first fluorous phase the first non-fluorous phase) in the methods of the present invention are less than the distribution coefficient of the first compound, resulting in faster transport of the first compound through the first fluorous phase. The distribution coefficient(s) of other compound(s) are preferably no greater than two times less than (or no greater than xc2xd of) the distribution coefficient of the first compound. More preferably, the distribution coefficient(s) of other compound(s) are no greater than five times less than (or no greater than ⅕ of) the distribution coefficient of the first compound. Most preferably, the distribution coefficient(s) of other compound(s) are no greater than ten times less than (or no greater than {fraction (1/10)} of) the distribution coefficient of the first compound.
Likewise, the distribution coefficient(s) of the second compound and other product compounds (as measured between the first fluorous phase and the second non-fluorous phase) in the methods of the present invention are less than the distribution coefficient of the first compound (as measured between the first fluorous phase the first non-fluorous phase) to minimize back transport of the second compound through the first fluorous phase. The distribution coefficients of the second compound and any other product compound are preferably no greater than two times less than (or no greater than xc2xd of) the distribution coefficient of the first compound. More preferably, the distribution coefficient of the second compound is no greater than five times less than (or no greater than ⅕ of) the distribution coefficient of the first compound. Most preferably, the distribution coefficient of the second compound is no greater than ten times less than (or no greater than {fraction (1/10)} of) the distribution coefficient of the first compound.
The first compound can, for example, include a fluorous group. Such a first compound can, for example, react with the third compound to produce the second compound, which is less fluorous in nature than the first compound. The reaction of the first compound and the third compound can also produce a fluorous compound (for example, a fluorous byproduct) which preferably distributes preferentially from the second non-fluorous phase into the fluorous phase, thereby being separated from the second compound which preferably distributes preferentially into the second non-fluorous phase. In general, the fluorous compound preferably has a distribution coefficient substantially greater than 1 (as measured between the first fluorous phase and the second non-fluorous phase). More preferably, the fluorous compound or byproduct has a distribution coefficient greater than 3. Most preferably, the fluorous compound or byproduct has a distribution coefficient greater than 10. If the fluorous byproduct is not separated from the second compound to a sufficient extent, other fluorous separation techniques (for example, liquid-liquid separation(s) and/or solid-liquid separation(s) can be used to effect separation. The method can also include the step of tagging the fluorous group onto a precursor compound to synthesize a fluorous-tagged first compound.
As used herein, the terms xe2x80x9cfluorous taggingxe2x80x9d or xe2x80x9cfluorous-taggedxe2x80x9d refers generally to attaching a fluorous moiety or group (referred to as a xe2x80x9cfluorous tagging moiety,xe2x80x9d xe2x80x9cfluorous tagging groupxe2x80x9d or simply xe2x80x9cfluorous tagxe2x80x9d) to a compound to create a xe2x80x9cfluorous-tagged compoundxe2x80x9d. Preferably, the fluorous tagging moiety is attached via covalent bond. However, other effective attachments such as ionic bonding, chelation or complexation can also be used. Fluorous tagging moieties facilitate separation of fluorous tagged compounds from other compounds as a result of differences in the fluorous nature of the compounds.
As used herein, the term xe2x80x9cfluorousxe2x80x9d, when used in connection with an organic (carbon-containing) molecule, moiety or group, refers generally to an organic molecule, moiety or group having a domain or a portion thereof rich in carbon-fluorine bonds (for example, fluorocarbons, fluorohydrocarbons, fluorinated ethers and fluorinated amines). The terms xe2x80x9cfluorous-tagged reagentxe2x80x9d or xe2x80x9cfluorous reagent,xe2x80x9d thus refer generally to a reagent comprising a portion rich in carbon-fluorine bonds. As used herein, the term xe2x80x9cperfluorocarbonsxe2x80x9d refers generally to organic compounds in which all hydrogen atoms bonded to carbon atoms have been replaced by fluorine atoms. The terms xe2x80x9cfluorohydrocarbonsxe2x80x9d and xe2x80x9chydrofluorocarbonsxe2x80x9d include organic compounds in which at least one hydrogen atom bonded to a carbon atom has been replaced by a fluorine atom. The attachment of fluorous moieties to organic compounds is discussed for example, in U.S. Pat. Nos. 5,859,247, 5,777,121, U.S. patent application Ser. No. 09/506,779, and U.S. Provisional Patent Application Serial No. 60/281,646, all assigned to the assignee of the present invention, the disclosures of which are incorporated herein by reference.
In another embodiment, the method further includes the step of contacting the second non-fluorous phase with a second fluorous phase at a third phase interface. In this embodiment, the method can also include the step of contacting the second fluorous phase with a third non-fluorous phase at a fourth phase interface. The method can thus include a series of reaction and/or separations as described above and below.
In another aspect, the present invention provides method of reacting a first compound to produce a second compound including the steps of: contacting a first non-fluorous phase including a first compound with a first fluorous phase at a first phase interface, the fluorous phase including at least one fluorous phase reagent that interacts with the first compound to form one or more fluorous intermediates; contacting the first fluorous phase with a second non-fluorous phase at a second phase interface; and including at least a third compound in the second non-fluorous phase that reacts with the fluorous intermediate or with the first compound to produce a product compound that preferably distributes preferentially in the second non-fluorous phase. The fluorous phase reagent preferably has a distribution coefficient (as, for example, measured between the fluorous phase and the first non-fluorous phase) of greater than approximately 1. More preferably, fluorous phase reagent preferably has a distribution coefficient greater than approximately 3. Most preferably, fluorous phase reagent preferably has a distribution coefficient greater than approximately 10. In general, the fluorous intermediate has a greater distribution coefficient than does the first compound.
The fluorous intermediate(s) can, for example, interact with the third compound in the fluorous phase (generally, in the vicinity of the second phase interface), at the second phase interface and/or in the second non-fluorous phase. The first compound can also be released by the fluorous intermediate(s) in the fluorous phase (generally, in the vicinity of the second phase interface), at the second phase interface and/or in the second non-fluorous phase wherein the first compound reacts with the third compound.
As used herein, the term xe2x80x9cinteractxe2x80x9d refers, for example, to a chemical reaction to form or break a chemical bond between the first compound and the fluorous reagent, to formation or breakage of another type of bond or attractive interconnection between the first compound and the fluorous phase reagent, or to micellar interrelation between the first compound and the fluorous reagent. For example, a covalent or ionic bond can be formed between the reagent and the first compound. Other types of bonds or attractive interactions include non-covalent bonds such as hydrogen bonding, dipole-dipole interactions and van der Waals forces. In general, any type of interaction, bond or attractive force that is suitably strong or durable to permit the fluorous intermediate to function as a unit for transport or to facilitate transport through the fluorous phase can be used. In general, the interaction between the first compound and the fluorous phase reagent acts to draw the first compound into the fluorous phase from the first non-fluorous phase and facilitates transport of the fluorous intermediate (for example, a first compound/fluorous reagent aggregate) toward the second organic phase.
The term xe2x80x9cfluorous phase reagent,xe2x80x9d as used herein refers generally to a chemical entity or physiochemical structure (for example, a micellar structure or particulate structure) that is suitable to interact with the first compound to form an intermediate entity or structure having a higher distribution coefficient than the first compound as described above. In one embodiment, the fluorous phase reagent can be a catalyst. For example, a fluorous catalyst that catalyzes a reaction between the second compound and the third compound can first form a fluorous complex with the first compound. The fluorous complex facilitates transport of the first compound through the fluorous phase toward the second organic phase. In other embodiments, the fluorous phase reagent can, for example, be a fluorous receptor, host or transport agent.
The first non-fluorous phase can include at least one compound other than the first compound. The other compound(s) preferably distribute preferentially into the first non-fluorous phase. The other compound(s) are preferably substantially non-reactive and non-interactive with the fluorous reagent. The interaction of the first compound with the reagent thus preferentially transports the first compound or other compounds derived from reaction thereof to the second non-fluorous phase via the first fluorous phase.
To carry out a series of reactions and/or separations as described here, the method can further include the step of contacting the second non-fluorous phase with a second fluorous phase at a third phase interface. The second fluorous phase can be contacted with a third non-fluorous phase at a fourth phase interface and so on.
Fluorous phase reagents can also be used to effect a separation with or without a reaction in the second non-fluorous phase. In that regard, the present invention provides in another aspect a method of separating a mixture of at least a first compound and a second compound comprising the steps of: contacting a first non-fluorous phase including the first compound and the second compound with a first fluorous phase at a first phase interface, the fluorous phase including a fluorous reagent that selectively interacts with the first compound to form a fluorous intermediate; and contacting the first fluorous phase with a second non-fluorous phase at a second phase interface.
The distribution coefficients of the second or other compounds in the first non-fluorous phase (as measured between the first fluorous phase and the first non-fluorous phase) are preferably no greater than two times less than (or no greater than xc2xd of) the distribution coefficient of the fluorous intermediate. More preferably, the distribution coefficients of the second or other compounds are no greater than five times less than (or no greater than ⅕ of) the distribution coefficient of the fluorous intermediate. Most preferably, the distribution coefficients of the second or other compounds are no greater than ten times less than (or no greater than {fraction (1/10)} of) the distribution coefficient of the fluorous intermediate.
In another aspect, the present invention provides a method of separating a mixture of at least a first compound and a second compound including the steps of: contacting a mixture of the of the first compound and the second compound in a first non-fluorous phase with a first fluorous phase at a first phase interface, the first compound distributing between the first fluorous phase and the first non-fluorous phase, the second compound having a distribution coefficient less than the first compound (and preferably distributing preferentially in the first non-fluorous phase); and contacting the fluorous phase with a second non-fluorous phase at a second phase interface.
The method can further include the step of selectively reacting a precursor compound with a fluorous tagging compound to produce the first compound, which is a fluorous-tagged compound.
The distribution coefficients of the second or other compounds in the first non-fluorous phase (as measured between the first fluorous phase and the first non-fluorous phase) are preferably no greater than two times less than (or no greater than xc2xd of) the distribution coefficient of the first compound. More preferably, the distribution coefficients of the second or other compounds are no greater than five times less than (or no greater than ⅕ of) the distribution coefficient of the first compound. Most preferably, the distribution coefficients of the second or other compounds are no greater than ten times less than (or no greater than {fraction (1/10)} of) the distribution coefficient of the first compound.
The method can also include the step of including at least third compound in the second non-fluorous phase that reacts with a fluorous-tagged first compound to produce a fourth compound of reduced fluorous nature compared to the first, fluorous-tagged compound, the fourth compound preferably distributing preferentially in the second non-fluorous phase. The fourth compound can be chemically the same as the precursor compound (that is, regeneration of the precursor compound) or chemically different from the precursor compound.
The method can also include the step of contacting the second non-fluorous phase with a second fluorous phase at a third phase interface. Once again, the second fluorous phase can be contacted with a third non-fluorous phase at a fourth phase interface and so on.
The methods of the present invention can, for example, be applied to separate a mixtures of enantiomers. Many stereoselective reactions, reagents and catalysts are known to those skilled in the art. For example, see Eliel, E. L.; Wilen, S. Stereochemistry of Organic Compounds; Wiley-Interscience: New York, 1994. Known and new reactions and reagents can be rendered fluorous or fluorous tagged as described herein and in U.S. Pat. Nos. 5,859,247, 5,777,121, U.S. patent application Ser. No. 09/506,779, and U.S. Provisional Patent Application Serial No. 60/281,646. In the methods of the present invention, at least one enantiomer of, for example, a racemic mixture of enantiomers can be preferentially converted to a fluorous or fluorous-tagged product. The reaction and/or separation methods of the present invention can then be used to separate the mixture.
In another aspect, the present invention provides an apparatus (for example, for separation and/or reaction of compounds) including a first non-fluorous phase in contact with a first fluorous phase at a first phase interface and a second non-fluorous phase in contact with the first fluorous phase at a second phase interface. Preferably, the first fluorous phase is a liquid phase.
The first non-fluorous phase can, for example, be in an upper portion of a first leg of a U-tube, the second non-fluorous phase can be in the upper portion of a second leg of the U-tube, and the first fluorous phase can be positioned within the U-tube between the first non-fluorous phase and the second non-fluorous phase. In one embodiment, the first non-fluorous phase includes a first stirring member therein, the first fluorous phase includes a second stirring member therein and the second non-fluorous phase includes a third stirring member therein. The stirring member can be used to perturb the phase interfaces to enhance exchange of certain components between the phases.
To carry out a series of reactions and/or separations as described herein, the second non-fluorous phase can be placed in contact with a second fluorous phase at a third phase interface, and the second fluorous phase can be placed in contact with a third non-fluorous phase at a fourth phase interface and so on.